Quinoxalinecarboxamide antiinflammatory agents

ABSTRACT

1,2,3,4-TETRAHYDRO - 1 - ACYL-3-OXO-2-QUINOXALINECARBOXAMIDES, A NOVEL CLASS OF HETERCYCLIC COMPOUNDS POSSESSING ANTINFLAMMATORY ACTIVITY.

Patented Apr. 4, 1972 QUINOXALINECARBOXAMIDE ANTIINFLAMMA- TORY AGENTSJames M. McManus, Old Lyme, Conn., assignor to Chas.

Pfizer & Co., Inc., New York, N.Y. No Drawing. Filed Oct. 15, 1969, Ser.No. 866,732

Int. Cl. C07d 51/78 US. Cl. 260-250 R 8 Claims ABSTRACT OF THEDISCLOSURE 1,2,3,4-tetrahydro 1 acyl-3-oXo-2-quinoxalinecarboxamides, anovel class of heterocyclic compounds possessing antiinflammatoryactivity.

BACKGROUND OF THE INVENTION The invention relates to1,2,3,4-tetrahydro-1-acyl-3- oxo-2-quinoxalinecarboxamides, a novelclass of heterocyclic compounds possessing chemotherapeutic activity.

Compounds of the present invention are synthesized via aminolysis of thecorresponding 2-carboalkoxyquinoxalines.

SUMMARY OF THE INVENTION The novel antiinflammatory compounds of thisinvention are quinoxalinecarboxarnides; in particular, they are 1,2,3,4tetrahydro 7 l acyl-3 oxo-2-quinoxalinecarboxamides of the formula:

and the basic metal salts thereof, \ivherein R and R are each selectedfrom the group consisting of hydrogen, alkyl containing up to 3 carbonatoms, fluorine, chlorine, bro- 'mine, 'alkoxy' and alkylthio each of upto 2 carbon atoms and hydroXy; R and R 'areeach selected from the group'consistin'gof hydrogen; alkyl containingup to 3 carbon atoms; allc'enylcontaining up 04* carbon atoms; cyclo alkyl of from 3 to 6 carbonatoms';-and phenyl andsubstituted phenyl having asub'stitu'erit selectedfrom the group'co'ns'isting of fluorine, chlorine,'bromine,"alkoxycontaining up to 2 carbon atoms and alkyl containing up to Jigbo t ms; Ris selected from the group consis of alkyl and alkenyl each ofup to 6carbon atoms; cycloalkyiof from 3 to- 6 carbon atoms;-.pyridyl.,andsubstituted pyridyl with 1 or Zrnethyl Isubstituents;,-.thiazoly1; andphenyl, benzyl and monoand disubstituted phenyl and benzyl, saidsubstituents being selected from the group consisting of fiuorine,chlorine, bromine, alkyl containing up to,3 carbon atoms, alkoxy an dalkylthio each having upto 2 carbon atoms,hydro xy,,amino, acylaminocontaining up to 3 .ca'rbon atoms, trifluoromethyl and tri- UnitedStates Patent Office Of particular interest are compounds wherein R andR are each hydrogen, R is methyl, R is either hydrogen or alkylcontaining up to 3 carbon atoms and R is substituted phenyl with 0 to 2substituents, said substituents being selected from the group consistingof fluorine, chlorine, bromine, alkyl containing up to 3 carbon atoms,alkoxy and alkylthio each having up to 2 carbon atoms, hydroxy, amino,acylamino containing up to 3 carbon atoms, trifluoromethyl andtrifluoromethoxy.

DETAILED DESCRIPTION OF THE INVENTION The quinoxalinecar-boxamides ofthe instant invention are prepared by several alternate procedures. Inthe procedure illustrated in Scheme I an appropiately substitutedo-phenylenediamine is reacted with a halomalonate ester to yield thequinoxaline ester, I.

preferable to use at least a molar equivalent amount of said reactantsand tertiary amine. The reaction is carried out at ambient temperatures,although it may be heated from about 50-80" C. to hasten productformation. Reaction time is not critical, but conversion is usuallycomplete within 2-5 hours, after which the product is isolated. Aconvenient means of isolation is to cool the reaction mixture, filterthe product and remove any coprecipitated tertiary amine hydrogen halidethrough a water wash. Alternately, the reaction mixture is added towater, which causes the product to precipitate.

The requisite o-phenylenediamines and halomalonate esters are availablecommercially or may be synthesized by one skilled in the art. Forexample, C. H. Roeder et al,. J. Org. Chem., 6', 25 (1941), teaches thepreparation of N-substituted-o-phenylenediamines and Palmer et al., Org.Syn. Coll., vol. I, 245 (1941), teaches the synthesis of a halomalonate.

Surprisingly, the condensation of the aforesaid o-phenylenediamines withhalomalonate esters gives a product resulting from cyclization and an insitu oxidation of 1,2,3,4-tetrahydroquinoxaline to a3,4-dihydroquinoxaline structure.

Products from the reaction of a o-phenylenediamine unsymmetricallysubstituted (R =H) in the aromatic moiety and a halomalonate ester giverise to two positional isomers, the separation of which is achievedusing thick layer or column chromatography. Structural assignments tothe separated isomers are readily carried out through the interpretationof their respective nuclear magnetic resonance spectra.

Reaction product from N-substituted-o-phenylenediamine (R H) and ahalomalonate ester, regardless of the substitution in the aromaticportion of the structure, are, almost exclusively, those resulting fromalkylation, followed by cyclization and oxidation, on the less hindered,primary amino group.

Reduction of the aforesaid 3,4-dihydroester, I, to II is carried out ina reaction-inert solvent such as ethanol or tetrahydrofuran, usinghydrogen gas and a catalytic amount of platinum oxide. Pressures of from2-50 psi. and temperatures of from 2550 C. may be employed. Thesepressure and temperature parameters are not critical, and influence onlyrate of product formation. The reaction product is best isolated byfiltration of the spent catalyst, and concentration of the filtrate todryness.

Acylation of the 1,2,3,4-tetrahydroquinoxaline ester, II, to provide IIImay be effected by adding an equimolar amount, plus as much as a 10%excess, of the corresponding acrylanhydride to II in a reaction-inertsolvent such as tetrahydrofuran or benzene. Reflux temperatures arepreferred, although lower temperatures may be used with correspondinglylonger reaction times. Removal of the solvent in vacuo leads to theisolation of the crude product, which is further purified byrecrystallization from appropriate solvents.

Aminolysis of III to the products of the instant invention, IV, iscarried out by heating III with a primary amine, R NH in a suitablesolvent such as benzene, toluene, mestitylene or tetraline for suchperiods of time as to allow for the formation of the desired product, ingeneral 5-10 hours. In instances when R NH is a high boiling amine, theformation of the product, IV, is facilitated by co-distilling thealcohol formed in the reaction with the solvent. Fresh solvent isperiodically added to maintain a relatively constant volume.- When R NHis low boiling the reaction is carried out using the. same solvents in a..sealed bomb or autoclave. Temperatures used in these reactions may,vary from 200 C. They are not critical, and reflect only on the rate ofproduct formation. Aconvenient means of isolation for the reactionproduct is to scam I:

l NR 1 N 00 0 co n o c NH CO2 r 0 ix 2 R R2 1' 4 1 comm I RSNHZ 5 -uoncomm v r u 1 I 5 v: (R3C0)20 INICONHR 1* l R The first step of Scheme IIis a condensation and cyclization of an appropriately substitutedo-phenylenediamine and an oxomalonate ester, the products of which arewater, an alcohol and I. The reaction is most conveniently carried outby adding an equimolar amount of the oxomalonate to a solution orsuspension of the suitable diamine in a reaction-inert solvent such asethanol. It is preferred that the reaction be heated from about 50-100C. for a period of 1-5 hours. The reaction product, which is identicalin every respect to I prepared via Scheme I, is isolated as aprecipitated solid after the reaction mixture is concentrated in volumeand cooled.

As in Scheme I, positional isomers are formed. They are separated andidentified by aforesaid procedures. Again, as in Scheme I, thecondensation of N-substitutedo-phenylenediamines with an oxomalonateester takes place preferentially on the unsubstituted --NH group.

Conversion of theester, I, to the carboxamide, V, is achieved by heatingI with as much as a three fold excess of the aforesaid amine, R NH in areaction-inert solvent such as dimethylformamide. When R NH is ,a lowboiling amine, a sealed bomb or autoclave is employed as the reactionvessel. Aminolysis of I to V is carried out at temperatures of fromIOU-200 C., with a preferred temperature of about C. The completion timefor the reaction is not critical, longer reaction periods being requiredwhen lower temperatures are used. Isolation of ,1 the product, as aprecipitate, is achieved by concentration of the reaction mixture involume, preferably in vacuo,

and cooling. a

Transformation of the 3,4-dihydroquinoxalinecarboxamide, V, to theproduct of the instant invention, IV, is carried out without isolationof the 1,2,3,4tetrahydrotion-inert solvent such as'tetrahydrofuran,using hydrogen gas and a catalytic amount of platinum oxide. Pressuresof from 2-50 p s.i. and temperatures of from 2550 C. are preferred. Whenthe theoretical amount of hydrogen has been absorbed, the spent catalystis filtered, and the filtrate containing VI is treated with at least anequimolar amount, and preferably a -20% excess, of an acylanhydride,"(-R CO) O-. It is preferred that the reaction be heated from between 50C. to the reflux temperature. The product precipitates after thereaction mixture is concentrated in vacuo, and cooled.

The final products from Schemes I and II are identical in every respect.

-It is noted that a common characteristic of many antiinflammatoryagents is that they contain an acidic hydrogen atom. Each of the3-carboxamides of the instant invention shares this property and is aneffective proton source, with the 'active hydrogen being located at the3-position.

Pharmaceutically acceptable, basic metal salts of the compoundsof-thepresent invention are also therapeutic agents, whereinthe cations ofsaid salts include the ammonium, sodium, potassium, calcium, andmagnesium ions. The pharmaceutically acceptable salts of the compoundsdescribed herein-are prepared by conventional procedures, *as for example, by adding the acid to an aqueous-solution containing anequivalent amount of a pharmaceuticallyacceptable base, i .e., a basecontaining one of the above cations, followed by concentration of theresultant mixtures to obtain the desired product. The bases may beselected from the hydroxides, oxides and carbonates. Pharmaceuticallyunacceptable, basic metal salts of the compounds of the presentinvention, wherein the cations of said salts include barium, strontium,cesium and rubidiumare also prepared by the aforementioned procedure.While said salts are not useful therapeutic agents per se, they arevaluable in the purification of the compounds of the present inventionand in the preparation of pharmaceutically acceptable salts.

As indicated hereinbefore, the 1,2,3,4-tetrahydro-1-acyl-3-oxo-2-quinoxalinecarboxamides and the pharmaceutically acceptablesalts thereof are useful antiinflammatory agents. These compounds are ofvalue in alleviating swelling and inflammation which are symptomatic ofrheumatoid arthritis and related disorders which are responsive totreatment with 'antiinfiammatory agents. Either as individualtherapeutic agents or as mixtures of therapeutic agents, they .may beadministered alone, but are generally-administered with a pharmaceuticalcarrier selected on the basis of the chosenroute of administration andstandard pharmaceutical practice. For example, they may beadministeredorally in the form of tablets or capsules containingsuchexcipients as starch, milk, sugar or certaintypes of clay, etc. Theymay be administered orallyin the formof elixirs or oral suspensions withthe active ingredients combined with emulsifying and/or suspendingagents. They may be injected parenterally, and for this use they, orappropriate derivatives, may be prepared in the form of sterile aqueoussolutions. Such aqueoussolution's should be suitably buffered, ifnecessary, and vshoul d. contain other solutes such as saline or glucoseto render them isotonic.

The dosage required to reduce inflammation or swelling in arthriticsubjects would be determined by the nature and extent of the symptoms.Generally, small doses will be" administered initially, with agradual-increase in the dosage until the optimum level is determined; Itwill generally be found that when the composition is administeredorally,p large r quantities of the active ingredient will be required toproduce the same level' as produced by a small quantity administeredparenterally. In general, from about 0.10 to about 200 mg. of activeingredient per kilogram of body weight,"administered in single ormultiple dose units, willefiectively reduce inflammation and swelling.

Particularly effective as antiinfiammatory agents are those carboxamidesof Formula IV wherein R and R are hydrogen, R is methyl, R is eitherhydrogen or alkyl containing up to 3 carbon atoms and R is phenyl withup to 2 substituents selected from the group consisting of fluorine,chlorine, bromine, alkyl containing up to 3 carbon atoms, alkoxy andalkylthio each having up to 2 carbon atoms, hydroxy, amino, acylaminocontaining up to 3 carbon atoms, trifluoromethyl and trifluoromethoxy.Among these compounds, 1,2,3,4-tetrahydro- 1acetyl-2',4-difluoro-3-oxo-2-quinoxalinecarboxanilide,1,2,3,4-tetrahydro 1 acetyl-3-oxo-4-methyl-4'-bromo-2-quinoxalinecarboxanilide and 1,2,3,4 tetrahydro-l-acetyl-3-oxo-4-ethyl-2-quinoxalinecarboxanilide are preferred.

A standard procedure for detecting and comparing antiinflammatoryactivity of compounds is the carrageenin rat foot edema test, wherebyunanesthetized adult male albino rats of 150-190 g. body weight are eachnumbered, weighed and marked with ink on the right lateral malleolus.One hour after administration of the drug by gavage, edema is induced byinjection of 0.05 ml. of 1% solution of carrageenin into the plantartissue of the marked paws. Immediately thereafter, the volume of theinjected paw is measured. The increase in volume three hours after theinjection of carrageenin constitutes the individual response. Compoundsare considered active if the difference in response between a controland the drug being tested is significant. Standard compounds arephenylbutazone at 33 mg./kg. and acetylsalicyclic acid at 100 mg./kg.,both with oral administration.

The following examples are given to more fully illustrate the instantinvention. They are not the only possible embodiments of the inventionand are not to be considered as a limitation on the scope thereof. Romannumerals in Examples 1 and II refer to structures in Schemes -I and II,respectively.

EXAMPLE I 3,4-dihydro-3-0xo-2-quinoxalinecarboxylic acid, ethyl ester(1; R R R =-H) 1,2,3,4-tetrahydro-3-oxo-2-quinoxalinecarboxylic acid,ethyl ester (II; R R R =H) A suspension of 2.18 g. (0.01 mole) of I and500 mg. of platinum oxide in 40 ml. of tetrahydrofuranis shaken in ahydrogen atmosphere at a pressure of 30 psi. for a period of two hours.The resulting reaction mixture is filtered, concentrated to dryness invacuo, and the residue slurried in water. The solid is filtered, driedand recrystallized from benzene, M.P. 148-149 C.

Analysis.Calcd. for C H N 0 (percent): C, 59.99; H, 5.49; N, 12.72.Found (percent): C, 59.77; H, 5.43; N, 12.75.

1,2,3,4-tetrahydro-1-acetyl-3-oxo-2-quinoxalinecarboxylic acid, ethylester (III; R R R =H; R =CH To a solution of 14.4 g. (0.065 mole) of nin ml. of tetrahydrofuran is added 7.14g. (0.07 mole) ofaceticanhydride. The reaction mixture is heated to. reflux 40 hours followedby removal of the solvent in vacuo. The residue is recrystallized fromethyl acetate-ether, M.P. 172174 C.

Analysis.Calcd. for C H N Q, (percent): C, 59.53; H, 5.38; N, 10.68.Found (percent): C, 59.28; H, 5.29; N, 10.73.

1,2,3,4tetrahydro-1-acetyl-2',5'-difiuoro-3-oxo-2-quinoxalinecarboxanilide (IV;R R R =H; R =CH3; 5= 2 e a) A mesityline (65 ml.) solution containing2.62 g. (0.01 mole) of III and 1.42 g. (0.011 mole) of2,5-difluoroaniline is heated to the boiling point. The mesitylene whichdistills off is gradually replaced by fresh solvent. When 110 ml. ofmesitylene has been distilled the reaction mixture is cooled, and thesolid which precipitates is filtered. The product is dried, andrecrystallized from ethyl acetate, M.P. 2092l0 C.

Analysis.-Calcd. for C17H13F2N3O3 (percent): C, 59.13; H, 3.79; N,12.17. Found (percent): C, 59.21; H, 3.94; N, 11.91.

EXAMPLE II 3,4-dihydro 3-oxo-2-quinoxalinecarboxylic acid, ethyl ester(I; R R R =H) To a suspension of o-phenylenediamine in ethanol is addedan equimolar amount of diethyl oxomalonate, and the resulting solutionis heated at steam bath temperatures for 1-2 hours. The resultingsolution is concentrated in vacuo and cooled. The desired product isfiltered, dried and recrystallized from benzene. The product isidentical to that synthesized by the procedures outlined in Example I.

To a suspension of I in dimethylformamide is added two molar equivalentsof 2,5-difluoroaniline, and the mixture is heated to the refluxtemperature for 6 hours. The reaction mixture is concentrated in vacuo,followed by cooling. The resulting product precipitates from solution,and is filtered. Further purification is carried out byrecrystallization from ethanol-water.

1,2,3,4-tetrahydro1-acetyl-2,5-difluoro-3-oxo-2-quinoxalinecarboxanilide (IV; R R R. =H; R=CH R5=2,5-F2C6H3) To a solution of V in tetrahydrofuran is addedplatinum oxide, and the resulting mixture shaken in a hydrogenatmosphere at an initial pressure of 50 p.s.i. for a period of 3 hours.The catalyst is filtered, and an equimolar amount of acetic anhydride isadded to the filtrate. The resulting solution is heated to the refluxtemperature for 1 hour, after which the reaction mixture is concentratedunder reduced pressure. On cooling, the desired product precipitatesfrom solution. Further purification is carried out by recrystallizationfrom benzene. The product is identical to that synthesized by theconditions outlined in Example I.

EXAMPLE 1H 1,2,3,4-tetrahydro-1-acety1-4'-bromo-3-0xo-2-quinoxalinecarboxanilide A suspension of 2.62 g. (0.01 mole) of1,2,3,4-tetrahydro-2-oxo-3-carbethoxy-4-acetylquinoxaline and 1.89 g.(0.011 mole) of 4-brornoaniline in 65 ml. of mesitylene is heated to theboiling point, and the mesitylene allowed to distill. After 23 ml. ofthe solvent is removed (2 hr.) a precipitate starts to form. Thereaction mixture is cooled, and the solid is filtered, 3.35 g., M.P.232243 8 C. The product is further purified by recrystallization fromacetonitrile, M.P. 258259 C.

Analysis.--Calcd. for C H BrN O (percent): C, 52.59; H, 3.63; N, 10.82.Found (percent): C, 52.91; H, 3.59; N, 10.85.

EXAMPLE IV The procedure of Example I is repeated, using equivalentamounts of appropriately substituted substrates, to produce thefollowing compounds:

1,2,3,4-tetrahydro-1-acetyl-3-oxo-4'-bromo-4-methyl-2-quinoxalinecarboxanilide A mixture of 1.89 g. (0.011 mole) ofp-bromoaniline and 2.76 g. (0.01 mole) of 1,2,3,4-tetrahydro-1-acetyl-3-oxo-4-methyl-2-quinoxalinecarboxylic acid, ethyl ester in ml. ofmesitylene is heated to the boiling point, and the solvent is allowed todistill. Fresh solvent is continually added such that the volume of thereaction mixture remains constant. This process is continued until 250ml. of solvent has been distilled. The reaction mixture is cooled, andthe precipitated solid collected by filtration, dried and recrystallizedfrom benzene.

EXAMPLE VI The procedure of Example V is repeated, using equivalentamounts of appropriately substituted substrates, to produce thefollowing compounds: I

1,2,3,4-tetrahydro-1-propiony1-3-oxo-4-ethyl-6-methoxy-2-quinoxalinecarboxanilide Q1,2,3,4-tetrahydro-1-acetyl-3-oxo-4-ethyl-7-methoxy-2-quinoxalinecarboxanilide1,2,3,4-tetrahydro-1-isobutyryl-3-oXo-4-ethyl-8methoxyquinoxalinecarboxanilide t1,2,3,4-tetrahydro-1-formyl-3-oxo-4-ethyl-5-methoxy2-quinoxalinecarboxanilide1,2,3,4-tetrahydro-1-acetyl-3-oxo-4-ethyl-6-methoxy-2-quinoxalinecarboxanilide 1,2,3,4-tetrahydro-1-acetyl-3-oxo-4-ethyl-8methoxy- 2-quinoxalinecarboxanilide I v v EXAMPLE VII The followingproducts are prepared by the procedure of Example VI, by substitutingthe appropriate starting materials:

0 1,2,3,4-tetrahydro-1-propionyl-3-oxo 4',7 dichloro-6--methyl2-quinoxalinecarboxanilide r 1,2,3,4-tetrahydrol propionyl-3'-oxo4' chloro-7- methyl-2-quinoxalinecarboxanilidev l H1,2,3,4-tetrahydro-1-propionyl-3-oxo-4'-chloro-5-ethyl-2-quinoxalinecarboxanilide 1,2,3, i-tetrahy dro-l=propionyl-3-oxo4-chloro-G-ethyllent amounts of appropriately substituted substrates, to

2-quinoxalinecarboxanilide. Y produce the following compounds:l,2,3,4-tetra hyd:ro-1 propionyl-3-oxo-4'-chl0ro-8-methyl- 2 quinoxalinecarboxanilide1,2,3,4-tetrahydro-1-propionyl-3-oxo-4'-chloro-7-npropyl-2-quinoxalinecarboxanilideEXAMPLE VIII The procedure of Example VI is-repeated, using equivalentamounts of v approximately substituted starting mao H "1 d th r11 d 1'sterla s, to pro uce e o owmg compoun s. C1 I R1 R2 R4 R5 G-methylHydrogen Methyl r. Ethyl. 7-methyl do. n-Hexyl. 2O fiethylm 7-methylCyclohexyl.

(i-n propy Hydrogen- Cyelopropyl. 5-methyl 7-methyl Methyl Methallyl.8-methyl Hydrogen n-Propyl. 2,2dimethyl-3- butenyl.

6-Cl fgCH S-Cl CH3 8-Cl CH S-F (Z-2H5, 6 F z s EXAMPLE XI S-Br 5 n-C H-1,2,3,4-tetrahydro-1-acetyl-3-oxo-quinoxaline-2-[N-(6- 5-OCH '1' n-C H-methyl-Z-pyridyl)]carboxamide 5-OCH .3, CH 5.00 11 A mixture of 1.19 g.(0.011 mole) of 2-amino-6-meth- H CH yl-pyridine and 2.62 g. (0.01 mole)of 1,2,3,4-tetrahydro- H t p 6 1 11-acetyl-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester in H i-C H 65ml. of mesitylene is heated to the boiling point. Fifty H 11 millilitersof the solvent is allowed to slowly distill from A the reaction mixtureand is replaced by 50 ml. of fresh I H EXAMPLE IX- solvent. This processis repeated until 265 ml. of mesityli f ene has been distilled. Theresulting solution is cooled, P o P V i eqmva' and the solid whichprecipitates is filtered and dried, 2.0 lent amounts ofappropnatelysubstituted substrates, to g My. 212.50 C. The purified product isobtained by recrystallization from ethanol, M.P. 230 C. dec.

Analysis.--Calcd. for C17H16N403 (percent): C, 62.95; H, 4.97; N, 17.28.Found (percent): C, 62.92; H, 5.02;

produce the following compounds;

g l p u I I N, 16.17.

. RB 1 v p 1 EXAMPLE XII The procedure of Example V is repeated, usingequivalent amounts of the appropriately substituted substrates, toprovide the following compounds:

., b 3 I I 0 R3 H 4-SOH: NE-R5 The procedure of Example H is repeated,usiugec uiva- EXAMPLE XIII The procedure of Example XII is repeated,using equivalent amounts of aniline in place of said heterocyclic amine,to produce the following compounds:

EXAMPLE XIV The procedure of Example I is repeated, using equivalentamounts of the appropriately substituted substrates, to produce thefollowing compounds:

EXAMPLE XV Sodium salt of l,2,3,4-tetrahydro-l-propionyl-3-oxo-2-quinoxalinecarboxanilide To a methanol solution of1,2,3,4-tetrahydro-1-propionyl-3-oxo-2-quinoxalinecarboxanilide isslowly added one equivalent of sodium hydroxide dissolved in a minimumamount of the same solvent. The resulting turbid 7 solution isconcentrated in vacuo, and the residue induced to solidifying bytrituration with ether.

EXAMPLE XVI tivity and were found to be active at the indicated doselevel:

What is claimed is 1. A compound selected from those of the formula:

and the basic metal salts thereof, wherein:

R and R are each selected from the group consisting of hydrogen, alkylcontaining up to'3 carbon atoms, fluorine, chlorine, bromine, alkoxy andalkylthio each of up to 2 carbon atoms and hydroxy; I R and R are eachselected from the group consisting of hydrogen; alkyl containing up to 3carbon atoms; alkenyl containing up to 4 carbon atoms; cycloalkyl offrom 3 to 6 carbon atoms; and phenyl and substituted phenyl having asubstituent selected from the group consisting of fluorine chlorine,bromine, alkoxy containing up to 2 carbonatoms and alkyl containing upto 3 carbon atoms; R is selected from the group consisting of alkyl andalkenyl each of up to 6 carbon atoms; cycloalkyl of from 3 to 6 carbonatoms; pyridyl and substituted pyridyl with 1 or 2 methyl substituents;thiazolyl; and phenyl, benzyl, and monoand disubstituted phenyl andbenzyl, said substitutents being selected from the group consisting offluorine, chlorine, bromine, alkyl containing up to 3 carbon atoms,alkoxy and alkylthio each having upto 2 carbon atoms, hydroxy, amino,acylamino'containing up to 3 carbon atoms, trifluoromethyl andtrifluoromethoxyl. 1 2. The compound of claim 1 wherein R and R arehydrogen, R is alkyl containing up to 4 carbon atoms and R is hydrogen.7 7 a c 3. The compound of claim 1 wherein R and R are hydrogen R ismethyl and R is alkyl containing up to 4 carbon atoms.

4. The compound of claim 1 wherein R is hydrogen, R is alkoxy of up to 2carbon atoms, R is ethyl and R is phenyl.

13 5. The compound of claim 1 wherein R is alkyl containing up to 4carbon atoms, R is ethyl, R is hydrogen and R is 4-chloropheny1.

6. The compound of claim 1 wherein R is 7-chloro,

R is methyl, R is alkyl containing up to 3 carbon atoms 5 and R is4'-methoxyphenyl.

7. 1,2,3,4-tetrahydro-1-acetyl-2,4'-difluoro 3 oX0-2-quinoxalinecarboxanilide.

8. 1,2,3,4-tetrahydro-1-acetyl-4' bromo 3 oxo- 4-methyl-2-quinoxalinecarboxanilide.

14 References Cited UNITED STATES PATENTS 3,479,348 11/1969 Yamamoto etal. 260-250 R NICHOLAS S. RIZZO, Primary Examiner US. Cl. X.R. 424250

